Reproduction and apoptosis of EBV- latent infected cells under influence a TRIZ-created antiviral drugs

Introduction. We had worked persistently and in 1997, the first model of such a structure based on oligopeptides of horse albumin was revealed. We named this project and called Albuvir (combined from the word Albumin and the word virus) and applied in veterinary medicine, where viral infections represent more than 95% of all pathologies. In 2000 an application was filed for the first modification of this drug. Subsequently, for the production and sale of this product, registration certificates of the State Committees in Veterinary Medicine of Eastern European countries were obtained.  In 2010, we signed a license agreement to transfer of limited rights in the field of veterinary medicine for the production and sale of Albuvir in Eastern Europe. The drug was produced commercially and was successfully used to cure hundreds of thousands of chickens, rabbits, sheeps, cows, pigs, pigeons, fish (industrial - sturgeon), cats, dogs, geese, ducks, and other types of farm birds and animals. Thus, the task of this work was to study the ability of Albuvir to inhibit EBV reproduction and induce apoptosis of latently infected cells in the culture. Materials and methods. Cell culture. The inhibitory effect of Albuvir on EBV was studied in the following cell cultures: Raji - cell culture of the B-phenotype of Burkitt's lymphoma. Namalwa is a B-phenotype cell culture from Burkitt's lymphoma that lacks the EBV genome. B95-8 is a marmoset monkey B-lymphocyte cell line containing the complete EBV genome, producing complete viral particles. To control cell viability, a 0.4% trypan blue dye (Sigma, United States) was used. EBV was isolated from a lymphoblastoid culture of B95-8 cells (B-lymphocytes of monkeys-marmazetka), which produces this virus, according to the method of Walls, Crawford. Investigated substances. Albuvir (N. 1) - dynamic acylated acidic peptides - antagonists of signal peptides of nuclear (nucleolar) localization and polyribosomes. Lysine tris-succinamide (N. 2). Acyclovir was used as a reference drug (references data)  MTT test. The cytotoxic concentration was determined in the Raji lymphoblastoid cell system using the colorimetric MTT method. This method is widely used to determine the CC50 of potential drugs in the study of the cytopathic action of viruses in vitro. Raji cells were plated into 96 well culture plates, 100 μl per well, 25 μl MTT (final concentration 5 μg / ml) was added and incubated for 3 h at 37 ° C in an atmosphere of 5% CO2. After incubation, cells were washed with PBS and resuspended in 96% ethanol to dissolve formazan. The results were analyzed spectrophotometrically on a Dynatech reader (Sweden) at a wavelength of 540 nm. Polymerase chain reaction. The degree of influence of drugs on EBV reproduction was determined using PCR test systems "AmpliSens-100-R". A fragment encoding the VCA protein of the virus with a size of 290 nucleotide sequences was the chosen genome region of the Epstein-Barr virus. The control was cells that, after infection with the virus, were incubated in the growth medium without the addition of the substances that were studied. We determined the percentage of inhibition of the level of accumulation of viral DNA in the samples treated with the test substances in relation to the control sample, the value of which was taken as 100%. Results and discussion. Effect of the dynamic antiviral drug Albuvir on reproduction and apoptosis latently infected with the Epstein-Barr virus cells in vitro. Modern approaches to the treatment of herpes infection, in particular the Epstein-Barr virus (EBV), include the use of ethyotropic drugs, as well as sensitizing therapy. The range of drugs active against EBV remains very limited to ganciclovir and acyclovir. The search for new compounds active against EBV remains relevant. The aim of this study was to find out the anti-EBV activity of the drug Albuvir in Raji, B95-8, Namalwa lymphoblastoid cells. The cytotoxicity index (CC50) was determined, which was 3000 ug/mL, and the concentration of the drug that inhibits the reproduction of the virus (EC50) was 0.1 ug/mL. The ability of the drug Albuvir to inhibit the reproduction of the Epstein-Barr virus in all studied cell cultures was revealed. When the economic efficiency of creating static drugs in accordance with the S-shaped curve decreases, the need arises for a transition to a supersystem, namely, the creation of dynamic drugs systems. It has been proven that the drug Albuvir is able to inhibit the reproduction of the Epstein-Barr virus in Raji, B95-8 and Namalwa cell cultures. It is determined that the drug has a high activity in the culture of Raji cells (SI 8400), respectively, the drug is promising enough to develop as a treatment for EBV-associated diseases.DOI: 10.5281/zenodo.403892

Pectus excavatum in motion: dynamic evaluation using real-time MRI.

OBJECTIVES The breathing phase for the determination of thoracic indices in patients with pectus excavatum is not standardized. The aim of this study was to identify the best period for reliable assessments of morphologic indices by dynamic observations of the chest wall using real-time MRI. METHODS In this prospective study, patients with pectus excavatum underwent morphologic evaluation by real-time MRI at 3 T between January 2020 and June 2021. The Haller index (HI), correction index (CI), modified asymmetry index (AI), and modified eccentricity index (EI) were determined during free, quiet, and forced breathing respectively. Breathing-related differences in the thoracic indices were analyzed with the Wilcoxon signed-rank test. Motion of the anterior chest wall was analyzed as well. RESULTS A total of 56 patients (11 females and 45 males, median age 15.4 years, interquartile range 14.3-16.9) were included. In quiet expiration, the median HI in the cohort equaled 5.7 (4.5-7.2). The median absolute differences (Δ) in the thoracic indices between peak inspiration and peak expiration were ΔHI = 1.1 (0.7-1.6, p .05 each). Furthermore, the dynamic evaluation revealed three distinctive movement patterns of the funnel chest. CONCLUSIONS Real-time MRI reveals patterns of chest wall motion and indicate that thoracic indices of pectus excavatum should be assessed in the end-expiratory phase of quiet expiration. KEY POINTS • The thoracic indices in patients with pectus excavatum depend on the breathing phase. • Quiet expiration represents the best breathing phase for determining thoracic indices. • Real-time MRI can identify different chest wall motion patterns in pectus excavatum

Study of forward Z + jet production in pp collisions at √s=7 TeV

A measurement of the $Z(\rightarrow\mu^+\mu^-)$+jet production cross-section in $pp$ collisions at a centre-of-mass energy $\sqrt{s} = 7$ TeV is presented. The analysis is based on an integrated luminosity of $1.0\,\text{fb}^{-1}$ recorded by the LHCb experiment. Results are shown with two jet transverse momentum thresholds, 10 and 20 GeV, for both the overall cross-section within the fiducial volume, and for six differential cross-section measurements. The fiducial volume requires that both the jet and the muons from the Z boson decay are produced in the forward direction ($2.0<\eta<4.5$). The results show good agreement with theoretical predictions at the second-order expansion in the coupling of the strong interaction.A measurement of the $Z(\rightarrow\mu^+\mu^-)$+jet production cross-section in $pp$ collisions at a centre-of-mass energy $\sqrt{s} = 7$ TeV is presented. The analysis is based on an integrated luminosity of $1.0\,\text{fb}^{-1}$ recorded by the LHCb experiment. Results are shown with two jet transverse momentum thresholds, 10 and 20 GeV, for both the overall cross-section within the fiducial volume, and for six differential cross-section measurements. The fiducial volume requires that both the jet and the muons from the Z boson decay are produced in the forward direction ($2.0<\eta<4.5$). The results show good agreement with theoretical predictions at the second-order expansion in the coupling of the strong interaction

Global Development of Research on Anorectal Malformations over the Last Five Decades: A Bibliometric Analysis

Purpose: Anorectal malformations (ARM) are one of the most challenging congenital malformations in pediatric surgery. We aimed to assess the research activity on ARM over the last five decades. Methods: Data on original research publications were retrieved from the Web of Science Core Collection (1970&ndash;2020), and analyzed for countries, authors, scientific journals, and top-ten papers. Scientific quantity was assessed by the number of publications. Research quality was estimated from the number of citations, average citation rate per item (ACI), and h-index. Results: A total number of 1595 articles with 19,419 citations (ACI = 12.2; h-index = 54) were identified. The annual number of publications and citations significantly increased over time (p &lt; 0.0001). The USA (n = 386; 24.2%), Japan (n = 153; 9.6%), and China (n = 137; 8.6%) were the most productive countries; and the USA (n = 7850; ACI = 20.3; h-index = 44), Japan (n = 1937; ACI = 12.6; h-index = 21), and the Netherlands (n = 1318; ACI = 17.3; h-index = 22) were the top cited countries. Articles were preferentially published in JPS (n = 391; 24.5%), PSI (n = 181; 11.3%), and EJPS (n = 56; 3.5%). Top-ten cited papers focused on classification (n = 1), surgical technique (n = 3), associated syndromes (n = 2), postoperative outcome (n = 3), and basic research (n = 1). Conclusion: This bibliometric study provides valuable insights into the global development of ARM research, and shows that clinical studies and international collaborations dominate in this field

Contemporary preclinical mouse models for pediatric rhabdomyosarcoma: from bedside to bench to bedside

Background: Rhabdomyosarcoma (RMS) is the most common pediatric softtissue malignancy, characterized by high clinicalopathological and molecular heterogeneity. Preclinical in vivo models are essential for advancing our understanding of RMS oncobiology and developing novel treatment strategies. However, the diversity of scholarly data on preclinical RMS studies may challenge scientists and clinicians. Hence, we performed a systematic literature survey of contemporary RMS mouse models to characterize their phenotypes and assess their translational relevance. Methods: We identified papers published between 01/07/2018 and 01/07/2023 by searching PubMed and Web of Science databases. Results: Out of 713 records screened, 118 studies (26.9%) were included in the qualitative synthesis. Cell line-derived xenografts (CDX) were the most commonly utilized (n = 75, 63.6%), followed by patient-derived xenografts (PDX) and syngeneic models, each accounting for 11.9% (n = 14), and genetically engineered mouse models (GEMM) (n = 7, 5.9%). Combinations of different model categories were reported in 5.9% (n = 7) of studies. One study employed a virus-induced RMS model. Overall, 40.0% (n = 30) of the studies utilizing CDX models established alveolar RMS (aRMS), while 38.7% (n = 29) were embryonal phenotypes (eRMS). There were 20.0% (n = 15) of studies that involved a combination of both aRMS and eRMS subtypes. In one study (1.3%), the RMS phenotype was spindle cell/sclerosing. Subcutaneous xenografts (n = 66, 55.9%) were more frequently used compared to orthotopic models (n = 29, 24.6%). Notably, none of the employed cell lines were derived from primary untreated tumors. Only a minority of studies investigated disseminated RMS phenotypes (n = 16, 13.6%). The utilization areas of RMS models included testing drugs (n = 64, 54.2%), studying tumorigenesis (n = 56, 47.5%), tumor modeling (n = 19, 16.1%), imaging (n = 9, 7.6%), radiotherapy (n = 6, 5.1%), long-term effects related to radiotherapy (n = 3, 2.5%), and investigating biomarkers (n = 1, 0.8%). Notably, no preclinical studies focused on surgery. Conclusions: This up-to-date review highlights the need for mouse models with dissemination phenotypes and cell lines from primary untreated tumors. Furthermore, efforts should be directed towards underexplored areas such as surgery, radiotherapy, and biomarkers

Pediatric Minimally Invasive Surgery&mdash;A Bibliometric Study on 30 Years of Research Activity

Background: Pediatric minimally invasive surgery (MIS) is a standard technique worldwide. We aimed to analyze the research activity in this field. Methods: Articles on pediatric MIS (1991&ndash;2020) were analyzed from the Web of Science&trade; for the total number of publications, citations, journals, and impact factors (IF). Of these, the 50 most cited publications were evaluated in detail and classified according to the level of evidence (i.e., study design) and topic (i.e., surgical procedure). Results: In total, 4464 publications and 53,111 citations from 684 journals on pediatric MIS were identified. The 50 most cited papers were published from 32 institutions in the USA/Canada (n = 28), Europe (n = 19), and Asia (n = 3) in 12 journals. Four authors (USA/Europe) contributed to 26% of the 50 most cited papers as first/senior author. Hot topics were laparoscopic pyeloplasty (n = 9), inguinal hernia repair (n = 7), appendectomy, and pyloromyotomy (n = 4 each). The majority of publications were retrospective studies (n = 33) and case reports (n = 6) (IF 5.2 &plusmn; 3.2; impact index 16.5 &plusmn; 6.4; citations 125 &plusmn; 39.4). They were cited as often as articles with high evidence levels (meta-analyses, n = 2; randomized controlled trials, n = 7; prospective studies, n = 2) (IF 12.9 &plusmn; 22.5; impact index 14.0 &plusmn; 6.5; citations 125 &plusmn; 34.7; p &gt; 0.05). Conclusions: Publications on laparoscopic pyeloplasty, inguinal hernia repair, appendectomy, and pyloromyotomy are cited most often in pediatric MIS. However, the relevant number of studies with strong evidence for the advantages of MIS in pediatric surgery is missing

Safety of tunneled central venous catheters in pediatric hematopoietic stem cell recipients with severe primary immunodeficiency diseases.

Tunneled central venous catheters (TCVCs) provide prolonged intravenous access for pediatric patients with severe primary immunodeficiency disease (PID) undergoing hematopoietic stem cell transplantation (HSCT). However, little is known about the epidemiology and clinical significance of TCVC-related morbidity in this particular patient group. We conducted the retrospective analysis of patients with severe PID who received percutaneous landmark-guided TCVC implantation prior to HSCT. We analyzed 92 consecutive TCVC implantations in 69 patients (median [interquartile range] age 3.0 [0-11] years) with severe combined immune deficiency (n = 39, 42.4%), chronic granulomatous disease (n = 17, 18.4%), and other rare PID syndromes (n = 36, 39.2%). The median length of TCVC observation was 144.1 (85.5-194.6) days with a total of 14,040 catheter days at risk (cdr). The overall rate of adverse events during catheter insertion was 17.4% (n = 16) and 25.0% during catheter dwell period (n = 23, catheter risk [CR] per 1000 cdr = 1.64). The most common complication was TCVC-related infection with an overall prevalence of 9.8% (n = 9, CR = 0.64), followed by late dislocation (n = 6, 6.5%, CR = 0.43), early dislocation (n = 4, 4.3%) and catheter dysfunction (n = 4, 4.3%, CR = 0.28). TCVCs are safe in children with severe PID undergoing HSCT with relatively low rates of TCVC-related infection